A new austenitic stainless steel with negligible nickel content: an in vitro and in vivo comparative investigation.
New nickel (Ni)-reduced stainless-steel metals have recently been developed to avoid sensitivity to Ni. In the present study, an austenitic Ni-reduced SSt named P558 (P558, Böhler, Milan, Italy) was studied in vitro on primary osteoblasts and in vivo after bone implantation in the sheep tibia, and was compared to ISO 5832-9 SSt (SSt) and Ti6Al4V. Cells were cultured directly on P558 and Ti6Al4V. Cells cultured on polystyrene were used as controls. Osteoblast proliferation, viability and synthetic activity were evaluated at 72 h by assaying WST1, alkaline phosphatase activity (ALP), nitric oxide, pro-collagen I (PICP), osteocalcin (OC), transforming growth factor-beta1 (TGFbeta-1) and interleukin-6 (IL-6) after 1.25(OH)2D3 stimulation. Under general anaesthesia, four sheep were submitted for bilateral tibial implantation of P558, SSt and Ti6Al4V rods. In vitro results demonstrated that the effect of P558 on osteoblast viability, PICP, TGF beta-1, tumor necrosis factor-alpha production did not significantly differ from that exerted by Ti6Al4V and controls. Furthermore, P558 enhanced osteoblast differentiation, as confirmed by ALP and OC levels, and reduced IL-6 production. At 26 weeks, the bone-to-implant contact was higher in P558 than in SSt (28%, p<0.005) and Ti6Al4V (4%, p<0.05), and was higher in Ti6Al4V than in SSt (22%, p<0.005). The tested materials did not affect bone microhardness in pre-existing host bone as evidenced by the measurements taken at 1000 microm from the bone-biomaterial interface (F=1.89, ns). At the bone-biomaterial interface the lowest HV value was found for SSt, whereas no differences in HV were observed between materials (F=1.55, ns). The current findings demonstrate P558 biocompatibility both in vitro and in vivo, and osteointegration processes are shown to be significantly improved by P558 as compared to the other materials tested.


Insulinomas may present with normoglycemia after prolonged fasting but glucose-stimulated hypoglycemia.
Insulinomas are rare but are the most common cause of hyperinsulinemic hypoglycemia in the adult population. Diagnosis of this pathology relies on clinical features along with laboratory tests and imaging investigations to aid in localization. One of the most robust standard tests used for establishing a biochemical diagnosis is the prolonged (72 h) fast. Currently, it is recommended that a prolonged supervised fast be performed, at least for 48 h if not for 72 h, and many would take the absence of hypoglycemia after a 72-h fast as evidence excluding the diagnosis. We employed prolonged fasts and standard glucose tolerance tests, plus imaging studies and surgical pathology, in two patients with suspected insulinomas. The prolonged 72-h fast was normal in both the patients, whereas in both cases a prolonged oral glucose tolerance test clearly demonstrated the induction of severe hyperinsulinemia followed by significant hypoglycemia. Surgical removal confirmed the presence of insulinomas in each case. Although the sensitivity of the 72-h fast is high and still plays an important role in the diagnosis of an insulinoma, we suggest that a "normal" test result should be interpreted in the light of clinical symptoms.


[Anatomopathological findings during development of diabetic cardiomyopathy in rats].
The diabetic cardiomyopathy occurs in both type 1 and type 2 diabetes mellitus. Hyperglycemia and associated metabolic changes participate in the pathogenesis of this disease. To characterizes various pathological changes occurring during the development of diabetic cardiomyopathy in rats. Diabetic rats were used for streptozotocin administration. At 7, 14, 21 and 30 days after toxic administration, the heart was obtained and placed in a Hartman solution and 4% p-formaldehyde. Five-micrometer thick sections were stained with hematoxylin-eosin, Masson trichrome and immunocytochemistry using anti-β-tubulin antibody. At 14 days after application of streptozotocin, dilated sinusoids with endothelial lining in the myocardium and collagen deposits in the cardiac interstitium and between the Purkinje fibers were observed. At 21 days there was a slight decrease of the arteriolar lumen due to hyperplasia of the medial layer. It is important to note that cardiac sinusoids as well as collagen deposits became more evident at 30 day of the study, as well as a major derangement of the microtubular system of the cardiomyocytes. Cardiac sinusoids representing fetal vascular pattern and interstitial fibrosis in the myocardium and the microtubular derangement of cardiomyocytes support the fact that the pathophysiological mechanism of diabetic cardiomyopathy begins in the coronary microcirculation due to changes in cardiac metabolism, contributing to the development of myocardial dysfunction in diabetes.


Comparison of Eleven RNA Extraction Methods for Poliovirus Direct Molecular Detection in Stool Samples.
Direct detection by PCR of poliovirus RNA in stool samples provides a rapid diagnostic and surveillance tool that can replace virus isolation by cell culture in global polio surveillance. The sensitivity of direct detection methods is likely to depend on the choice of RNA extraction method and sample volume. We report a comparative analysis of 11 nucleic acid extraction methods (7 manual and 4 semiautomated) for poliovirus molecular detection using stool samples (n = 59) that had been previously identified as poliovirus positive by cell culture. To assess the effect of RNA recovery methods, extracted RNA using each of the 11 methods was tested with a poliovirus-specific reverse transcription-quantitative PCR (RT-qPCR), a pan-poliovirus RT-PCR (near-whole-genome amplification), a pan-enterovirus RT-PCR (entire capsid region), and a nested VP1 PCR that is the basis of a direct detection method based on nanopore sequencing. We also assessed extracted RNA integrity and quantity. The overall effect of extraction method on poliovirus PCR amplification assays tested in this study was found to be statistically significant (P < 0.001), thus indicating that the choice of RNA extraction method is an important component that needs to be carefully considered for any diagnostic based on nucleic acid amplification. Performance of the methods was generally consistent across the different assays used. Of the 11 extraction methods tested, the MagMAX viral RNA isolation kit used manually or automatically was found to be the preferable method for poliovirus molecular direct detection considering performance, cost, and processing time. IMPORTANCE Poliovirus, the causative agent of poliomyelitis, is a target of global eradication led by the World Health Organization since 1988. Direct molecular detection and genomic sequencing without virus propagation in cell culture is arguably a critical tool in the final stages of polio eradication. Efficient recovery of good-quality viral RNA from stool samples is a prerequisite for direct detection by nucleic acid amplification. We tested 11 nucleic acid extraction methods to identify those facilitating sensitive, fast, simple, and cost-effective extraction, with flexibility for manual and automated protocols considered. Several different PCR assays were used to compare the recovered viral RNA to test suitability for poliovirus direct molecular detection. Our findings highlight the importance of choosing a suitable RNA extraction protocol and provide useful information to diagnostic laboratories and researchers facing the choice of RNA extraction method for direct molecular virus detection from stool.


The past and present threat of rickettsial diseases to military medicine and international public health.
Morbidity and mortality caused by rickettsioses have had a major influence on military activities and public health for >2000 years. The threat posed by the rickettsioses is reviewed, focusing on the impact and epidemiology of those that have adversely influenced wartime operations and the current challenges posed by these diseases. With their uneven worldwide distribution, the discovery of drug-refractory strains of Orientia tsutsugamushi, the increased threat of their use in acts of bioterrorism, frequent deployment of troops to regions of endemicity, and exposures due to increased humanitarian missions, these diseases continue to be a threat to military personnel in the field. Effective strategies to reduce the impact of these diseases include development of effective vaccines, enhanced surveillance, and development of new safe, effective, and odorless repellants. The continuation of a proven, highly productive military infectious disease research program is essential for providing solutions to these daunting tasks.


Clinical and genetic aspects of termination of pregnancy; tertiary center experience.
The aim of the study was to retrospectively analyze the indications Techniques and complications of pregnancy termination performed in a tertiary center. All cases between 10 and 33 weeks of gestation between January 2021 and June 2023 were retrospectively analyzed. The patients were divided into two groups as group 1 with 11+0 to 21+6 gestational weeks and group 2 for those at 22+0 and 33+0 gestational weeks. A total of 568 pregnancy terminations were included in the study. Among all terminations the most common fetal indications were central nervous system anomalies (148 cases, 26%) and trisomy 21 (53 cases, 9%) and the most common maternal/obstetrical Indication was previable premature rupture of the membranes (179 cases, 31.5%). Abnormal genetic results were found in 50 of 173 cases (28.9%) with a termination indication of Structural malformation who accepted invaziv genetic testing. The number of terminations with fetal indications performed after 22 weeks were 148 (41%) and 11 (7.4%) cases of these late terminations of pregnancy were anomalies expected to be diagnosed in the first trimester. Complication rates (12.4%) and abdominal termination rates (3.5%) were significantly higher in group 2 than in group 1 (p<0.05). Improvements in prenatal genetic screening and diagnostic techniques will undoubtedly decrease the gestational ages in terminations of pregnancies. However, there will always be cases that can neither be diagnosed earlier nor can be treated due to the nature of the anomaly. In the management of such cases, terminations will always occupy an important place in prenatal care.


Histamine-containing cells from bronchial lavage of macaque monkeys. Time course and inhibition of anaphylactic histamine release.
Bronchial lavage of rhesus and cynomolgus monkeys provided leucocyte suspensions with viable histamine-containing cells (HCC) as 1--8% of the white cell population. These HCC released histamine or challenge with antiserum to human IgE. HCC from 2 monkeys with pulmonary and cutaneous hypersensitivity to Ascaris antigen (AA) released histamine on challenge with AA. The extent of histamine release was related to the concentration of antigen and antiserum, and histamine release was complete within 10 min of challenge. (+/-)Salbutamol and (-)isoprenaline were potent inhibitors of anaphylactic histamine release from HCC, but disodium cromoglycate and AH 9679 were relatively poor inhibitors. The HCC system combines the reproducibility of a cell suspension with a response to drugs similar to that of human lung fragments.


Elevated GTP Cyclohydrolase I Pathway in Endothelial Progenitor Cells of Overweight Premenopausal Women.
Background/Aims. Sexual differences exist in endothelial progenitor cells (EPCs), and various cardiovascular risk factors are associated with the preservation of endothelial function in premenopausal women. However, it is unclear whether differences in endothelial function and circulating EPCs exist between overweight premenopausal women and age-matched men. Methods. We compared EPC counting and functions in normal-weight and overweight premenopausal women and men, evaluated endothelial function in each group, and detected the expression of the guanosine triphosphate cyclohydrolase I (GTPCH I) pathway. Results. The number of EPCs was lower in the male group than in the female group, regardless of normal-weight or overweight status, and there was no significant difference between the different weight groups among females or males. Endothelial function and EPC migration and proliferation were preserved in overweight premenopausal women compared with overweight men as were nitric oxide (NO) levels in plasma and secreted by EPCs. Endothelial function, the circulating EPC population, and NO levels were not different between normal-weight and overweight premenopausal women. Flow-mediated dilatation was significantly correlated with EPC function, plasma NO levels, and EPC-secreted NO. Conclusions. This investigation provides the first evidence for sex-based differences in EPC activity and endothelial function in overweight middle-aged individuals; these differences are associated with alterations in NO production and may partly occur through downregulation of the GTPCH I pathway. The present results provide new insights into the mechanism underlying the preserved endothelial function in overweight premenopausal women and may uncover a potential therapeutic target for endothelial repair in overweight population.


Postapplication Fipronil Exposure Following Use on Pets.
Fipronil is a pyrazole acaricide and insecticide that may be used for insect, tick, lice, and mite control on pets. Residents' short-term and long-term postapplication exposures to fipronil, including secondary environmental exposures, were estimated using data from chemical-specific studies. Estimations of acute (24-h) absorbed doses for residents were based on U.S. Environmental Protection Agency (U.S. EPA) 2012 standard operating procedures (SOPs) for postapplication exposure. Chronic exposures were not estimated for residential use, as continuous, long-term application activities were unlikely to occur. Estimated acute postapplication absorbed doses were as high as 0.56 μg/kg-d for toddlers (1-2 yr) in households with treated pets based on current U.S. EPA SOPs. Acute toddler exposures estimated here were fivefold larger in comparison to adults. Secondary exposure from the household environment in which a treated pet lives that is not from contacting the pet, but from contacting the house interior to which pet residues were transferred, was estimated based on monitoring socks worn by pet owners. These secondary exposures were more than an order of magnitude lower than those estimated from contacting the pet and thus may be considered negligible.


The role of the hippocampus in memory for the temporal order of a sequence of odors.
Memory for the temporal order of a sequence of odors was assessed in rats. A sequence of 5 odors mixed in sand was presented in digging cups, 1 at a time, to each rat in a sequence that varied on each trial. A reward was buried in each cup. After the 5th odor, 2 of the previous 5 odors were presented simultaneously; to receive a reward, the rat had to choose the odor that occurred earliest in the sequence. Temporal separations of 1, 2, or 3 represented the number of odors that occurred between the 2 odors in the sequence. Once a preoperative criterion was reached, each rat received a hippocampal (HIP) or cortical control lesion and was retested on the task. On postoperative trials, the HIP group was impaired relative to controls. However, the HIP group could discriminate between the odors. The data suggest that the hippocampus is involved in separating sensory events in time so that I event can be remembered separately from another event.


Membrane morphology is actively transformed by covalent binding of the protein Atg8 to PE-lipids.
Autophagy is a cellular degradation pathway involving the shape transformation of lipid bilayers. During the onset of autophagy, the water-soluble protein Atg8 binds covalently to phosphatdylethanolamines (PEs) in the membrane in an ubiquitin-like reaction coupled to ATP hydrolysis. We reconstituted the Atg8 conjugation system in giant and nm-sized vesicles with a minimal set of enzymes and observed that formation of Atg8-PE on giant vesicles can cause substantial tubulation of membranes even in the absence of Atg12-Atg5-Atg16. Our findings show that ubiquitin-like processes can actively change properties of lipid membranes and that membrane crowding by proteins can be dynamically regulated in cells. Furthermore we provide evidence for curvature sorting of Atg8-PE. Curvature generation and sorting are directly linked to organelle shapes and, thus, to biological function. Our results suggest that a positive feedback exists between the ubiquitin-like reaction and the membrane curvature, which is important for dynamic shape changes of cell membranes, such as those involved in the formation of autophagosomes.


A Computational Model of Cn2 Profile Inversion for Atmospheric Laser Communication in the Vertical Path.
In this paper, an atmospheric structure constant Cn2 model is proposed for evaluating the channel turbulence degree of atmospheric laser communication. First, we derive a mathematical model for the correlation between the atmospheric coherence length r0, the isoplanatic angle θ0 and Cn2 using the Hufnagel-Valley (HV) turbulence model. Then, we calculate the seven parameters of the HV model with the actual measured r0 and θ0 data as input quantities, so as to draw the Cn2 profile and the θ0 profile. The experimental results show that the fitted average Cn2 contours and single-day Cn2 contours have superior fitting performance compared with our historical data, and the daily correlation coefficient between the single-day computed θ0 contours and the measured θ0 contours is up to 87%. This result verifies the feasibility of the proposed method. The results validate the feasibility of the proposed method and provide a new technical tool for the inversion of turbulence Cn2 profiles.


A novel fiber-optic photometer for in situ stability assessment of concentrated oil-in-water emulsions.
The purpose of this research was to evaluate a novel fiber-optic photometer for its ability to monitor physical instabilities occurring in concentrated emulsions during storage. For this, the fiber-optic photometer was used to measure transmission of oil-in-water emulsions stabilized with hypromellose (HPMC) as a function of oil volume fraction and droplet size distribution (DSD). To detect physical instabilities like creaming and coalescence, the transmissivity of the samples was studied at 2 different height levels over a certain period of time. The corresponding droplet size distributions were determined by laser diffraction with PIDS. Transmissivity was found to depend on the number of dispersed droplets and thus is sensitive to both the variation of phase volume fraction as well as the emulsions droplet size distribution. At constant DSD, light transmission decreased linearly with increasing oil content within a large interval of phase volume fractions from 0.01 to 0.3. At constant phase volume fraction, an increase in droplet size increased light transmission. Investigation of creaming on emulsions with different droplet size distributions showed changes in the initial delay times and creaming velocities. In contrast to creaming phenomenon coalescence can be identified by height independent changes of the transmissivity. In conclusion, transmissivity of oil-in-water emulsions observed by the novel fiber-optic photometer is sensitive to phase volume fraction, droplet size distribution, and thus can be used as a tool for stability studies on concentrated emulsions.


Quality and consumer decision making in the market for health insurance and health care services.
This article reviews the literature relating quality to consumer choice of health plan or health care provider. Evidence suggests that consumers tend to choose better performing health plans and providers and are responsive to initiatives that provide quality information. The response to quality and quality information differs significantly among consumers and across population subgroups. As such the effect of quality information on choice is apparent in only a relatively small, though perhaps consequential, number of consumers. Despite the wealth of findings on the topic to date, the authors suggest directions for future work, including better assessment of the dynamic issues related to information release, as well as a better understanding of how the response to information varies across different groups of patients.


Toward clinical understanding of aristolochic acid upper-tract urothelial carcinoma.
A cluster of patients poisoned by herbal medicine in the 1990s revealed that aristolochic acid (AA) causes kidney failure and upper tract urothelial carcinoma (UTUC). Recent research demonstrated that this was not an isolated incident; on the contrary, AA exposure is widespread in East Asia. This editorial highlights research by Lu and colleagues that investigates clinical characteristics of AA and non-AA UTUCs from 90 patients in Beijing based on the AA mutational signature. The study also detected AA mutations in non-tumor tissue of AA exposed patients and showed that AA mutations can be detected in urine, which might form the basis for non-invasive tests for AA exposure.


Gender and the cultural construction of good and bad suicides.
Some cultures distinguish two or more types of suicide which are evaluated differently. The more acceptable or esteemed ones are often not equally accessible to everyone within the same society. This article focuses on gender differences in the cultural construction of suicide options, and on the exclusion of women from superior options. The analysis is based on ethnographic and historical data from Native Americans of the Great Plains, Muslim societies in Southeast Asia, and tribal societies in the Amazon area of South America.


Cerebral metabolism and the electroencephalogram during hypocapnia plus hypotension induced by sodium nitroprusside or trimethaphan in dogs.
The effects on cerebral metabolism and the electroencephalogram (EEG) of combining hypocapnia with hypotension have been only incompletely examined. The present study examined the possibility that hypocapnia may worsen the cerebral metabolic and EEG disturbances caused by hypotension. Cerebral metabolism and the EEG were studied at three levels of hypotension during hypocapnia (PaCO2 = 20 mm Hg) in dogs under light halothane anesthesia. A sequential decrease of the mean arterial pressure (MAP) to 60, 50, and 40 mm Hg (30 minutes at each level) was achieved with sodium nitroprusside (SNP) (n = 12) or trimethaphan (TMP) (n = 12). With SNP-induced hypotension plus hypocapnia, the power of the alpha and beta 2 spectra of the EEG decreased at MAP less than or equal to 60 mm Hg. Cerebral metabolic values were unchanged at a MAP of 60 or 50 mm Hg. Brain tissue phosphocreatine and the cerebral energy charge decreased, and the lactate/pyruvate ratio increased at a MAP of 40 mm Hg. With TMP-induced hypotension plus hypocapnia, power decreased in the alpha and beta 2 spectra of the EEG at MAP less than or equal to 60 mm Hg. Cerebral metabolic values were unchanged at a MAP of 60 mm Hg. At MAP less than or equal to 50 mm Hg, power in the beta 1 spectrum, brain tissue phosphocreatine, and the cerebral energy charge all decreased. At a MAP of 40 mm Hg, the cerebral glucose value decreased and the lactate/pyruvate ratio increased.(ABSTRACT TRUNCATED AT 250 WORDS)


Ketamine in Critically Ill Patients: Use, Perceptions, and Potential Barriers.
Objective: To evaluate practitioner use of ketamine and identify potential barriers to use in acutely and critically ill patients. To compare characteristics, beliefs, and practices of ketamine frequent users and non-users. Methods: An online survey developed by members of the Society of Critical Care Medicine (SCCM) Clinical Pharmacy and Pharmacology Section was distributed to physician, pharmacist, nurse practitioner, physician assistant and nurse members of SCCM. The online survey queried SCCM members on self-reported practices regarding ketamine use and potential barriers in acute and critically ill patients. Results: Respondents, 341 analyzed, were mostly adult physicians, practicing in the United States at academic medical centers. Clinicians were comfortable or very comfortable using ketamine to facilitate intubation (80.0%), for analgesia (77.9%), procedural sedation (79.4%), continuous ICU sedation (65.8%), dressing changes (62.4%), or for asthma exacerbation and status epilepticus (58.8% and 40.4%). Clinicians were least comfortable with ketamine use for alcohol withdrawal and opioid detoxification (24.7% and 23.2%). Most respondents reported "never" or "infrequently" using ketamine preferentially for continuous IV analgesia (55.6%) or sedation (61%). Responses were mixed across dosing ranges and duration. The most common barriers to ketamine use were adverse effects (42.6%), other practitioners not routinely using the medication (41.5%), lack of evidence (33.5%), lack of familiarity (33.1%), and hospital/institutional policy guiding the indication for use (32.3%). Conclusion: Although most critical care practitioners report feeling comfortable using ketamine, there are many inconsistencies in practice regarding dose, duration, and reasons to avoid or limit ketamine use. Further educational tools may be targeted at practitioners to improve appropriate ketamine use.


Renal solitary fibrous tumour: A rare pathological entity.
A solitary fibrous tumour (SFT) is a rare mesenchymal cell neoplasm that can develop at any site. SFT of the kidney is extremely rare. Recently, we had a case of solitary fibrous tumour involving the left kidney in a 71-year-old female patient. The SFT was incidentally found by imaging modalities at the time of a physical workup. Computed tomography and retrograde pyelography showed a 4 × 3.5 × 4-cm nodular mass in the middle poles of the left kidney adjacent to the renal pelvis. A laparoscopic radical resection of the left kidney was performed. The tumour was well-circumscribed and composed of a mixture of spindle cells; microscopically, we found dense collagenous bands. Immunohistochemical studies showed strong reactions with CD34, bcl-2 and CD99. A nuclear positivity with Ki-67 was observed in less than 1% of cells. The tumour was negative for desmin, SMA and CD117. Histopathological and immunohistochemical studies confirmed the diagnosis of a solitary fibrous tumour.


Differences in carbonate chemistry up-regulation of long-lived reef-building corals.
With climate projections questioning the future survival of stony corals and their dominance as tropical reef builders, it is critical to understand the adaptive capacity of corals to ongoing climate change. Biological mediation of the carbonate chemistry of the coral calcifying fluid is a fundamental component for assessing the response of corals to global threats. The Tara Pacific expedition (2016-2018) provided an opportunity to investigate calcification patterns in extant corals throughout the Pacific Ocean. Cores from colonies of the massive Porites and Diploastrea genera were collected from different environments to assess calcification parameters of long-lived reef-building corals. At the basin scale of the Pacific Ocean, we show that both genera systematically up-regulate their calcifying fluid pH and dissolved inorganic carbon to achieve efficient skeletal precipitation. However, while Porites corals increase the aragonite saturation state of the calcifying fluid (Ωcf) at higher temperatures to enhance their calcification capacity, Diploastrea show a steady homeostatic Ωcf across the Pacific temperature gradient. Thus, the extent to which Diploastrea responds to ocean warming and/or acidification is unclear, and it deserves further attention whether this is beneficial or detrimental to future survival of this coral genus.


Hepatic lipocytes, TIMP-1 and liver fibrosis.
In progressive liver fibrosis, the rate [corrected] of extracellular collagen deposition exceeds its rate of degradation. Collagen and related proteins are synthesised in the fat-storing liver cells (lipocytes). When injured, these cells proliferate and change into myofibroblast-like cells, secreting even more collagen into the extracellular space. The degradation of collagen is accomplished by metalloproteinases, whose activity is reduced by tissue inhibitors (TIMPs). Injured lipocytes produce an excess of these inhibitors. The final result of lipocyte injury is thus progressive liver fibrosis. There is evidence that TIMPs also play a role in progressive fibrosis in other tissues.


[Nijmegen Breakage syndrome].
Nijmegen Breakage syndrome is a rare, autosomal recessive disorder characterized by severe, combined immunodeficiency, recurrent sinopulmonary infections, chromosomal instability, radiosensitivity, predisposition to malignancy, a "bird-like" facial appearance, progressive microcephaly, short stature, and mental retardation. The syndrome is caused by mutations in the NBS1 gene, which encodes a DNA-repair protein, named nibrin. The authors summarize current knowledge on molecular genetics, diagnostic characteristics and therapeutic options of this inborn error of innate immunity.


Plasmon-Enhanced Electrochemiluminescence of Silver Nanoclusters for microRNA Detection.
Surface plasmon-enhanced electrochemiluminescence (SPEECL) with excellent sensitivity and simplicity has attracted increasing attention. In this work, we reported a novel SPEECL with DNA templated silver nanoclusters (DNA-AgNCs) as ECL emitters and gold nanoparticles (AuNPs) as localized surface plasmon resonance (LSPR) source. The SPEECL with DNA-AgNCs as ECL luminophores possessed low toxicity and avoided the labeling process, which is favorable for its further sensing application. In addition, by investigation of the SPEECL under different distances between DNA-AgNCs and AuNPs, it was demonstrated that the SPEECL was distance dependent. Meanwhile, the SPEECL intensity changed with the sizes and interdistance of AuNPs under different electrodeposition time. Furthermore, by the combination of a cyclic amplification process with enzyme-free catalytic hairpin DNA, a sensitive SPEECL biosensor was proposed for the detection of microRNA (miRNA-21) successfully with a wide linear range from 1 aM to 104 fM and a relatively low detection limit of 0.96 aM, which was applied in the detection of miRNA-21 in real samples with satisfying results. This novel, simple, sensitive, and selective SPEECL with label-free and low-toxic ECL emitters displayed a great potential for bioassay application.


Intestinal ion transport and intracellular pH during acute respiratory alkalosis and acidosis.
Acute respiratory alkalosis and acidosis alter rat ileal and colonic but not jejunal electrolyte transport. To examine the role of altered intracellular pH, pHi, and HCO3 concentration, (HCO3)i, we measured pHi in mucosa scraped from the jejunum, ileum, and colon of anesthetized, mechanically ventilated Sprague-Dawley rats. During states of respiratory alkalosis (Pco2 24.9 +/- 0.8 mmHg, pH 7.586 +/- 0.014), respiratory acidosis (Pco2 67.8 +/- 1.2 mmHg, pH 7.228 +/- 0.007), and normocapnia (Pco2 41.1 +/- 0.7 mmHg, pH 7.401 +/- 0.006), pHi was measured by determining the distribution of 5,5-dimethyl[2-14C]oxazolidine-2,4-dione, using [3H]inulin as a marker of extracellular space. (HCO3)i was calculated using portal vein Pco2. In the ileum, the pHi of 6.901 +/- 0.029 was similar in alkalosis [(HCO3)i 5.4 +/- 0.3 mM], acidosis [(HCO3)i 12.4 +/- 0.6 mM], and normocapnia [(HCO3)i 8.6 +/- 0.8 mM). In both the jejunum and colon, pHi was increased in alkalosis [pHi 6.998 +/- 0.038, (HCO3)i 6.7 +/- 0.6 mM] and decreased in acidosis [pHi 6.789 +/- 0.024, (HCO3)i 10.4 +/- 0.6 mM] as compared with normocapnia [pHi 6.915 +/- 0.026, (HCO3)i 8.9 +/- 0.7 mM] (colon data given). Net electrolyte transport measured by in vivo perfusion revealed that ileal and colonic, but not jejunal, net Na and Cl absorption was decreased during alkalosis and increased during acidosis. These data suggest that, during respiratory acidosis and alkalosis, pHi is maintained in a qualitatively similar way in the jejunum, ileum, and colon with quantitatively greater or lesser changes in (HCO3)i.(ABSTRACT TRUNCATED AT 250 WORDS)


An activated protein C analog with reduced anticoagulant activity extends the therapeutic window of tissue plasminogen activator for ischemic stroke in rodents.
Tissue plasminogen activator (tPA) is the only approved therapy for acute ischemic stroke. However, tPA has a brief therapeutic window. Its side effects include intracerebral bleeding and neurotoxicity. Therefore, a combination therapy with tPA and agents that can extend the therapeutic window of tPA and/or counteract its side effects are warranted. Here, we studied whether 3K3A-APC, a neuroprotective analog of activated protein C with reduced anticoagulant activity, can enhance the therapeutic effects of tPA in models of ischemic stroke in rodents. Human recombinant tPA (10 mg/kg), alone or in combination with human recombinant 3K3A-APC (2 mg/kg), was administered intravenously 4 hours after proximal or distal transient middle cerebral artery occlusion in mice and embolic stroke in rats. The 3K3A-APC was additionally administered for 3 to 4 consecutive days after stroke. The neuropathological and neurological analyses were performed at 1 to 7 days after stroke. In all models, tPA alone had no effects on the infarct volume or behavior (ie, neurological score, foot-fault, forelimb asymmetry, adhesive removal) compared with vehicle. The tPA and 3K3A-APC combination therapy reduced the infarct volume 24 hours and 7 days after proximal or distal transient middle cerebral artery occlusion in mice and 7 days after embolic stroke in rats by 65%, 63%, and 52%, respectively, significantly (P<0.05) improved behavior and eliminated tPA-induced intracerebral microhemorrhages. The 3K3A-APC extends the therapeutic window of tPA for ischemic stroke in rodents. Therefore, this combination therapy also should be considered for treating stroke in humans.


How I Do It: Inferior Turbinectomy: Modified Techniques for Submucosal Resection.
Although inferior turbinectomy with submucosal resection effectively reduces the volume of the inferior turbinate, there is room for improvement in surgical procedures. Techniques have been developed to reduce crusting and bleeding while efficiently achieving volume reduction. State-of-the-art procedures pertaining to the local injection site, incision line, exposure of the periosteum, submucosal outfracture of the turbinate bone, trimming of redundant mucosa, and incision line suturing are described. Pre and postoperative Nasal Obstruction Symptom Evaluation (NOSE) scores and postoperative inferior turbinate bleeding and crusting were evaluated. For the 18 consecutive patients analyzed, the pre and postoperative NOSE scores were 67.8 ± 14.8 and 16.1 ± 13.0, respectively (P = .0002). Postoperatively, bleeding was absent, and only minor suture thread crusting was observed in 13 patients. In conclusion, our novel technique improves the effectiveness of surgery as well as the postoperative quality of the inferior turbinate.


Anthropometry and dietary intake of type 2 diabetes patients attending an outpatient clinic.
A cross sectional study on Type 2 diabetes patients seeking treatment in the Primary Health Care outpatient clinic of the University Malaya Medical Centre, Kuala Lumpur was undertaken. Two hundred and thirty-three subjects participated. They were asked questions on biodata and dietary intake using face-to-face interview techniques. Dietary intake was assessed using the 24-hour dietary recall. Anthropometric measurements including weight and height were taken and Body Mass Index (BMI) was computed to establish the extent of obesity. Of the 196 subjects, 66.8% were overweight (BMI ≥25 kg/m2) with 15.8% obese (BMI ≥30 kg/m2). The mean BMI of males and females were 25.9±4.3 kg/m2 and 27.2±4.7 kg/m2 respectively. The findings from the dietary survey showed that the mean energy intake of the subjects only achieved about 72% of the Recommended Daily Allowance (RDA) for Malaysia while protein intake of all subjects was adequate. The macronutreint contribution to the total calorie was consistent with the recommendation of the Malaysian Diabetic Association for a healthy diet for diabetes patients. The male subjects were found to meet the RDA requirements for all nutrients while the female subjects did not have sufficient intake of calcium, vitamin A and niacin. No consistent pattern in energy and nutrient intake was observed among different age groups. On the other hand, the Malay subjects seemed to have lower energy and all nutrient intake (except vitamin A and vitamin C) compared to the Chinese and Indian subjects. The Indian subjects seemed to have the highest intake of calcium compared to the others. Advice needs to be given to those who did not have adequate nutrient intake as well as those who need to reduce their weight.


Anterior ischemic optic neuropathy associated with udenafil.
We report a case of anterior ischemic optic neuropathy associated with udenafil. A 54-year-old male presented with an acute onset visual field defect of the right eye after udenafil use. Examination revealed a relative afferent pupillary defect and a swollen disc. Automated visual fields revealed an enlarged blind spot and a narrowed visual field. Fluorescein angiography revealed both an inferior choroidal filling delay and an inferior sector filling delay of the optic disc in the arteriovenous phase as well as diffuse leakage of the optic disc in the late phase. Optical coherent tomography revealed increased thickness of the retinal nerve fiber layer, especially in the area of the inferior disc. The patient was counseled to discontinue the use of udenafil and to monitor his blood pressure regularly. The disc swelling was resolved with residual optic atrophy one month after discontinuing the use of udenafil.


The secreted aspartic proteinases as a new target in the therapy of candidiasis.
Secreted aspartic proteinases (Saps) are important virulence factors in different types of candidiasis caused by Candida albicans (C. albicans). The various isoenzymes are expected to fulfil different tasks during mucosal or disseminated infections. It could be shown that the introduction of the proteinase inhibitors like saquinavir and indinavir in the therapy of human immunodeficiency virus (HIV) infected patients has an effect on Sap activity in vitro as well as in vivo. Therefore, drugs like the HIV proteinase inhibitors could play an essential role in the treatment of candidiasis in the future, especially if further adapted to this target.


A pH-Mediated Topological Switch within the N-Terminal Domain of Human Caveolin-3.
Caveolins mediate the formation of caveolae, which are small omega-shaped membrane invaginations involved in a variety of cellular processes. There are three caveolin isoforms, the third of which (Cav3) is expressed in smooth and skeletal muscles. Mutations in Cav3 cause a variety of human muscular diseases. In this work, we characterize the secondary structure, dynamics, and topology of the monomeric form of the full-length lipidated protein. Cav3 consists of a series of membrane-embedded or surface-associated helical elements connected by extramembrane connecting loops or disordered domains. Our results also reveal that the N-terminal domain undergoes a large scale pH-mediated topological rearrangement between soluble and membrane-anchored forms. Considering that roughly one-third of pathogenic mutations in Cav3 influence charged residues located in this domain, we hypothesize that this transition is likely to be relevant to the molecular basis of Cav3-linked diseases. These results provide insight into the structure of Cav3 and set the stage for mechanistic investigations of the effects of pathogenic mutations.


Alzheimer's disease in Down syndrome: neurobiology and risk.
Down syndrome (DS) is characterized by increased mortality rates, both during early and later stages of life, and age-specific mortality risk remains higher in adults with DS compared with the overall population of people with mental retardation and with typically developing populations. Causes of increased mortality rates early in life are primarily due to the increased incidence of congenital heart disease and leukemia, while causes of higher mortality rates later in life may be due to a number of factors, two of which are an increased risk for Alzheimer's disease (AD) and an apparent tendency toward premature aging. In this article, we describe the increase in lifespan for people with DS that has occurred over the past 100 years, as well as advances in the understanding of the occurrence of AD in adults with DS. Aspects of the neurobiology of AD, including the role of amyloid, oxidative stress, Cu/ZN dismutase (SOD-1), as well as advances in neuroimaging are presented. The function of risk factors in the observed heterogeneity in the expression of AD dementia in adults with DS, as well as the need for sensitive and specific biomarkers of the clinical and pathological progressing of AD in adults with DS is considered.


2,8-dihydroxyadenine urolithiasis: report of a case first diagnosed after renal transplant.
We report a case of homozygous adenine phosphoribosyl transferase (APRT) deficiency associated with 2,8-dihydroxyadenine stones recurrent in a patient with a renal transplant. The disease was diagnosed 23 years after the initial episode of renal colic. At that time the disease was unknown. Our patient is only the second case of this disorder reported from the United States. Correct diagnosis is important because long-term maintenance with allopurinol and a low purine diet can effectively prevent stone formation and renal failure.


Mono-ADP-ribosyltransferase as a potential pharmacological drug target in the GLP-1 based therapy of obesity and diabetes mellitus type 2.
Glucagon-like peptide-1 (GLP-1) based therapy is well established for treating diabetes mellitus type 2. Moreover, GLP-1 receptor agonists influence weight loss, and have potential for treating obesity. GLP-1 receptor agonists should be administered in low doses, together with drugs that potentiate insulin release, to avoid some minor side effects. We have focused on incretin hormones, especially GLP-1 and its analogues. Here we discuss the effect of the third intracellular loop-derived peptide of GLP-1 receptor on intracellular mono-ADP-ribosyltransferase and its role in regulating the receptor. We suggest that this intracellular mono-ADP-ribosyltransferase could constitute a possible novel pharmacological target in the treatment of diabetes mellitus type 2 and obesity.


Molecular mechanisms of TSD in reptiles: a search for the magic bullet.
Significant progress has been made in understanding mechanisms of genetic sex determination. The ZFY gene encodes a zinc finger protein but is not the primary signal in sex determination. The SRY gene is the testis determining gene in man, mouse, rabbit, and probably marsupial mouse and wallaby. Temperature dependent sex determination probably involves a modification of development of the indifferent gonad due to differential expression of one or more specific DNA sequences whose behavior is controlled by some temperature sensitive process or to differential action of a gene product such as a protein. There are ZFY and SRY-like genes in reptiles. We cloned and sequenced a portion of the ZFY gene (Zft) from snapping turtle (Chelydra serpentina) that is found in both sexes. We cloned and sequenced portions of SRY-like genes (Sra for SRY-related-autosomal) from snapping turtle. Similar genes are found in alligator (Alligator mississippiensis) and lizards. Cladistic analysis suggests that there are two or three major families of SRY-like genes in vertebrates in addition to sex specific SRY genes located on the Y chromosome of eutherian and marsupial mammals. When placed on a phylogenetic tree these data indicate that Sras were present in early tetrapods. Sequestering of the SRY gene on the Y chromosome probably happened only once and this may have been the defining moment that set the mammalian line of Therapsid reptiles apart from other reptilian groups.


Origin and evolution of the mitochondrial aminoacyl-tRNA synthetases.
Many theories favor a fusion of 2 prokaryotic genomes for the origin of the Eukaryotes, but there are disagreements on the origin, timing, and cellular structures of the cells involved. Equally controversial is the source of the nuclear genes for mitochondrial proteins, although the alpha-proteobacterial contribution to the mitochondrial genome is well established. Phylogenetic inferences show that the nuclearly encoded mitochondrial aminoacyl-tRNA synthetases (aaRSs) occupy a position in the tree that is not close to any of the currently sequenced alpha-proteobacterial genomes, despite cohesive and remarkably well-resolved alpha-proteobacterial clades in 12 of the 20 trees. Two or more alpha-proteobacterial clusters were observed in 8 cases, indicative of differential loss of paralogous genes or horizontal gene transfer. Replacement and retargeting events within the nuclear genomes of the Eukaryotes was indicated in 10 trees, 4 of which also show split alpha-proteobacterial groups. A majority of the mitochondrial aaRSs originate from within the bacterial domain, but none specifically from the alpha-Proteobacteria. For some aaRS, the endosymbiotic origin may have been erased by ongoing gene replacements on the bacterial as well as the eukaryotic side. For others that accurately resolve the alpha-proteobacterial divergence patterns, the lack of affiliation with mitochondria is more surprising. We hypothesize that the ancestral eukaryotic gene pool hosted primordial "bacterial-like" genes, to which a limited set of alpha-proteobacterial genes, mostly coding for components of the respiratory chain complexes, were added and selectively maintained.


Decrease of disease-related metabolites upon fasting in a hemizygous knock-in mouse model (Mut-ko/ki) of methylmalonic aciduria.
Methylmalonyl-CoA mutase (MMUT) is part of the propionyl-CoA catabolic pathway, responsible for the breakdown of branched-chain amino acids, odd-chain fatty acids and the side-chain of cholesterol. Patients with deficient activity of MMUT suffer from isolated methylmalonic aciduria (MMAuria), frequently presenting in the newborn period with failure to thrive and metabolic crisis. Even well managed patients remain at risk for metabolic crises, of which one known trigger is acute illness, which may lead to poor feeding and vomiting, putting the patient in a catabolic state. This situation is believed to result in increased breakdown of propionyl-CoA catabolic pathway precursors, producing massively elevated levels of disease related metabolites, including methylmalonic acid and propionylcarnitine. Here, we used fasting of a hemizygous mouse model (Mut-ko/ki) of MMUT deficiency to study the role of induced catabolism on metabolite production. Although mice lost weight and displayed markers consistent with a catabolic state, contrary to expectation, we found strongly reduced levels of methylmalonic acid and propionylcarnitine in fasted conditions. Switching Mut-ko/ki mice from a high-protein diet to fasted conditions, or from a standard diet to a no-protein diet, resulted in similar reductions of methylmalonic acid and propionylcarnitine levels. These results suggest, in our mouse model at least, induction of a catabolic state on its own may not be sufficient to trigger elevated metabolite levels.


Mutational analysis of the carbohydrate-binding activity of the NeuAc(alpha-2,6)Gal/GalNAc-specific type 2 ribosome-inactivating protein from elderberry (Sambucus nigra) fruits.
Sambucus nigra agglutinin I (SNA-I) is a type 2 ribosome-inactivating protein. Site-directed mutagenesis was used to mimic the conversion of the highly active B-chain of fruit-specific SNA (SNA-If) into the completely inactive B-chain of the closely related and naturally occurring loss-of-activity mutant called S. nigra agglutinin lectin-related protein. In the first mutant SNA-If-M1 the high-affinity site 2 of SNA-If was disrupted by replacing the presumed critical residue Asp231 with Glu231. In the double mutant SNA-If-M2, site 1 of SNA-If-M1 was also disrupted by substituting the presumed critical residue Asn48 with Ser48. The parent type 2 ribosome-inactivating protein and both mutants were expressed in Nicotiana tabacum Samsun NN and the recombinant proteins were purified and analysed. Recombinant SNA-If agglutinated rabbit erythrocytes equally well as SNA-If, but both mutants were completely inactive in this test. Binding assays to immobilized galactose and fetuin revealed that the mutation Asp231-->Glu231 reduces the affinity of the B-chain for galactose and fetuin by more than 50%. Furthermore, the introduction of the second mutation Asn48-->Ser48 reduces the binding activity to less than 20% of the original activity.


Novel 1, 2, 4-Triazoles as Antifungal Agents.
The development of innovative antifungal agents is essential. Some fungicidal agents are no longer effective due to resistance development, various side effects, and high toxicity. Therefore, the synthesis and development of some new antifungal agents are necessary. 1,2,4-Triazole is one of the most essential pharmacophore systems between five-membered heterocycles. The structure-activity relationship (SAR) of this nitrogen-containing heterocyclic compound showed potential antifungal activity. The 1,2,4-triazole core is present as the nucleus in a variety of antifungal drug categories. The most potent and broad activity of triazoles have confirmed them as pharmacologically significant moieties. The goal of this review is to highlight recent developments in the synthesis and SAR study of 1,2,4-triazole as a potential fungicidal compound. In this study, we provide the results of a biological activity evaluation using various structures and figures. Literature investigation showed that 1, 2, 4-triazole derivatives reveal the extensive span of antifungal activity. This review will assist researchers in the development of new potential antifungal drug candidates with high effectiveness and selectivity.


Crystal plane-integrated strontium oxide/hexagonal boron nitride nanohybrids for rapid electrochemical sensing of anticancer drugs in human blood serum samples.
In this work, the crystal plane of strontium oxide (SrO) nanorods was integrated into hexagonal-boron nitride (h-BN) nanosheets to form 1D-2D (SrO/h-BN) composite were utilized for the electrochemical detection of the chemotherapeutic drug 5-fluorouracil (5-Fu). 5-Fu is a clinically proven and the third most frequently applied chemotherapeutic drug for treating solid tumours, such as colorectal, stomach, cutaneous and breast malignancies. Its overdoses lead to toxic metabolite accumulation that has serious adverse consequences on humans, including neurotoxicity, death and the induction of morbidity. Therefore, to improve the chemotherapy and predict the potential adverse effects of 5-Fu residues in the human body, susceptible and quick analytical methods for detecting 5-Fu in human body fluids (blood serum/plasma and urine) are needed. The effective interaction of the synthesized SrO/h-BN composite shows increased efficiency for the electrochemical detection of 5-Fu with good selectivity. Notably, a simple sonochemical method achieved a synergistic interaction between the (100) plane of SrO and the (002) plane of h-BN. Various analytical and spectroscopic techniques were used to characterize the SrO/h-BN nanocomposite, which provided useful insights into the composition and properties of the composite material. The crystalline, structural and chemical characteristics of the as-synthesized material were characterized by XRD, Raman spectroscopy, HR-TEM, XPS and HR-SEM. Furthermore, the proposed electrode's electrochemical sensing capability was analysed using CV, EIS, DPV and i-t curve methods. Numerous active sites created on a modified electrode enhanced the mass transport and electron transfer rate, thereby increasing the electrochemical activity towards the 5-Fu detection. Consequently, under optimized conditions, the SrO/h-BN/GCE exhibited remarkable selectivity, durability, low detection limit (0.003 μM) and wide linear range (0.02-56 μM) for 5-Fu. Finally, the successful application of this sensor for 5-Fu detection in biological samples was successfully tested with high recovery percentages.


Sporothrix schenckii sensu stricto and Sporothrix brasiliensis Are Differentially Recognized by Human Peripheral Blood Mononuclear Cells.
Sporothrix schenckii sensu stricto and S. brasiliensis are usually associated to sporotrichosis, a subcutaneous mycosis worldwide distributed. Comparative analyses between these two species indicate they contain genetic and physiological differences that are likely to impact the interaction with host cells. Here, we study the composition of the cell wall from conidia, yeast-like cells and germlings of both species and found they contained the same sugar composition. The carbohydrate proportion in the S. schenckii sensu stricto wall was similar across the three cell morphologies, with exception in the chitin content, which was significantly different in the three morphologies. The cell wall from germlings showed lower rhamnose content and higher glucose levels than other cell morphologies. In S. brasiliensis, the wall sugars were constant in the three morphologies, but glucose was lower in yeast-like cells. In S. schenckii sensu stricto cells most of chitin and β1,3-glucan were underneath wall components, but in S. brasiliensis germlings, chitin was exposed at the cell surface, and β1,3-glucan was found in the outer part of the conidia wall. We also compared the ability of these cells to stimulate cytokine production by human peripheral blood mononuclear cells. The three S. schenckii sensu stricto morphologies stimulated increased levels of pro-inflammatory cytokines, when compared to S. brasiliensis cells; while the latter, with exception of conidia, stimulated higher IL-10 levels. Dectin-1 was a key receptor for cytokine production during stimulation with the three morphologies of S. schenckii sensu stricto, but dispensable for cytokine production stimulated by S. brasiliensis germlings. TLR2 and TLR4 were also involved in the sensing of Sporothrix cells, with a major role for the former during cytokine stimulation. Mannose receptor had a minor contribution during cytokine stimulation by S. schenckii sensu stricto yeast-like cells and germlings, but S. schenckii sensu stricto conidia and S. brasiliensis yeast-like cells stimulated pro-inflammatory cytokines via this receptor. In conclusion, S. brasiliensis and S. schenckii sensu stricto, have similar wall composition, which undergoes changes depending on the cell morphology. These differences in the cell wall composition, are likely to influence the contribution of immune receptors during cytokine stimulation by human monocytes.


Eliminating financial disincentives to living kidney donation - a call to action.
The incidence of end stage renal disease (ESRD) in the United States (US) is increasing each year. The lone curative treatment for ESRD remains kidney transplantation. Despite the demonstrated medical and economic benefits, living donor kidney transplantation (LDKT) only accounts for a small number of kidney transplantations each year. Direct and indirect costs exist that disincentivize potential living kidney donors from coming forward, such as the cost of travel and lodging, risk of death, potential loss of income due to an extended recovery time, and the inability to donate to a relative in the future if needed. Herein, we advocate for policy changes that make living kidney donation (LKD) a financially neutral process thereby incentivizing increased LDKT and mitigating the kidney donor shortage.


Hydrophilic interaction and reversed-phase ultra-performance liquid chromatography TOF-MS for metabolomic analysis of Veratrum nigrum-induced cardiotoxicity.
The acute cardiotoxicity induced by Veratrum nigrum (VN) is explored by analyzing heart tissue metabolic profiles in mouse models and applying reversed-phase liquid chromatography mass spectrometry and hydrophilic interaction liquid chromatography mass spectrometry that are based on ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry. An animal model of acute heart injury was established in mice via intra-gastric administration of VN. Then, electrocardiogram and echocardiograph monitoring of cardiac function and pathological examination were performed on mice in both the control and VN groups, and it was verified that acute heart injury was caused. Meanwhile, comparing the results of the control and VN groups, we detected 36 differential endogenous metabolites of heart tissue, including taurine, riboflavin, purine and lipids, which are related to many possible pathways such as purine metabolism, taurine and hypotaurine metabolism and energy metabolism. Our study provides a scientific approach for evaluating and revealing the mechanisms of VN-induced cardiotoxicity via the metabolomic strategy.


Hedgehog antagonist REN(KCTD11) regulates proliferation and apoptosis of developing granule cell progenitors.
During the early development of the cerebellum, a burst of granule cell progenitor (GCP) proliferation occurs in the outer external granule layer (EGL), which is sustained mainly by Purkinje cell-derived Sonic Hedgehog (Shh). Shh response is interrupted once GCPs move into the inner EGL, where granule progenitors withdraw proliferation and start differentiating and migrating toward the internal granule layer (IGL). Failure to interrupt Shh signals results in uncoordinated proliferation and differentiation of GCPs and eventually leads to malignancy (i.e., medulloblastoma). The Shh inhibitory mechanisms that are responsible for GCP growth arrest and differentiation remain unclear. Here we report that REN, a putative tumor suppressor frequently deleted in human medulloblastoma, is expressed to a higher extent in nonproliferating inner EGL and IGL granule cells than in highly proliferating outer EGL cells. Accordingly, upregulated REN expression occurs along GCP differentiation in vitro, and, in turn, REN overexpression promotes growth arrest and increases the proportion of p27/Kip1+ GCPs. REN also impairs both Gli2-dependent gene transcription and Shh-enhanced expression of the target Gli1 mRNA, thus antagonizing the Shh-induced effects on the proliferation and differentiation of cultured GCPs. Conversely, REN functional knock-down impairs Hedgehog antagonism and differentiation and sustains the proliferation of GCPs. Finally, REN enhances caspase-3 activation and terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling apoptotic GCP numbers; therefore, the pattern of REN expression, its activity, and its antagonism on the Hedgehog pathway suggest that this gene may represent a restraint of Shh signaling at the outer to inner EGL GCP transitions. Medulloblastoma-associated REN loss of function might withdraw such a limiting signal for immature cell expansion, thus favoring tumorigenesis.


Evaluation of lactic dehydrogenase in cases of meningitis.
Lactic dehydrogenase (LDH) was measured serially in cerebrospinal fluid (CSF) and serum in 23 cases of meningitis (15 pyogenic and 8 tuberculous) and equal number of age and sex matched healthy controls to find out its diagnostic and prognostic significance in cases of meningitis. The LDH activity was significantly elevated in the CSF and serum (p < 0.001) in cases of pyogenic (PM) as well as tuberculous meningitis (TBM). The maximum elevation was seen on the 1st day and the activity declined thereafter. However, in 3 cases of PM and 5 cases of TBM, the LDH activity on subsequent estimations increased serially and all these cases died. Further, the basal LDH activity in the 3 cases of PM who died was significantly higher (p < 0.01) than those who survived. The rise in enzymatic activity in the CSF was significantly higher (p < 0.001) than in the serum in all the cases of meningitis. The LDH activity was significantly higher in PM as compared to TBM (p < 0.001) both in the CSF as well as the serum.


Metallic W/WO2 solid-acid catalyst boosts hydrogen evolution reaction in alkaline electrolyte.
The lack of available protons severely lowers the activity of alkaline hydrogen evolution reaction process than that in acids, which can be efficiently accelerated by tuning the coverage and chemical environment of protons on catalyst surface. However, the cycling of active sites by proton transfer is largely dependent on the utilization of noble metal catalysts because of the appealing electronic interaction between noble metal atoms and protons. Herein, an all-non-noble W/WO2 metallic heterostructure serving as an efficient solid-acid catalyst exhibits remarkable hydrogen evolution reaction performance with an ultra-low overpotential of -35 mV at -10 mA/cm2 and a small Tafel slope (-34 mV/dec), as well as long-term durability of hydrogen production (>50 h) at current densities of -10 and -50 mA/cm2 in alkaline electrolyte. Multiple in situ and ex situ spectroscopy characterizations combining with first-principle density functional theory calculations discover that a dynamic proton-concentrated surface can be constructed on W/WO2 solid-acid catalyst under ultra-low overpotentials, which enables W/WO2 catalyzing alkaline hydrogen production to follow a kinetically fast Volmer-Tafel pathway with two neighboring protons recombining into a hydrogen molecule. Our strategy of solid-acid catalyst and utilization of multiple spectroscopy characterizations may provide an interesting route for designing advanced all-non-noble catalytic system towards boosting hydrogen evolution reaction performance in alkaline electrolyte.


Group II phospholipase A2 mRNA synthesis is stimulated by two distinct mechanisms in rat vascular smooth muscle cells.
Two potent inflammatory mediators, interleukin 1 (IL-1) and tumor necrosis factor (TNF) as well as lipopolysaccharide (LPS) increased group II phospholipase A2 (PLA2) mRNA levels, which resulted in enhanced secretion of the PLA2 enzyme from rat smooth muscle cells. cAMP-elevating agents also stimulated the release of PLA2 and increased the mRNA, but IL-1, TNF and LPS did not affect cAMP levels. Furthermore, the effects of TNF and cAMP-elevating agents were not additive but synergistic. Therefore, we concluded that the level of rat group II PLA2 mRNA is controlled at least by two distinct mechanisms, one involves cAMP and the other is mediated by TNF, IL-1 and LPS. This study also suggests important roles of group II PLA2 in pathogenesis of vascular inflammation.


Juvenile laryngeal papillomatosis: report of five cases from Papua New Guinea.
Five cases of juvenile laryngeal papillomatosis encountered in Papua New Guinea during the period from December 1987 to May 1989 are described in detail. They were seen in the age-range of 1 year 7 months-5 years. The common clinical features were change of voice and dyspnoea. They were treated by microlaryngoscopic excision with cupped forceps. One of the cases followed-up for 15 months showed multiple recurrences. This condition of juvenile laryngeal papillomatosis, though not common, is certainly not rare in this country and should be considered as a differential diagnosis in the case of a child presenting with progressive dyspnoea.


Detection of Wuchereria bancrofti DNA in paired serum and urine samples using polymerase chain reaction-based systems.
The Global Program for the Elimination of Lymphatic Filariasis (GPELF) aims to eliminate this disease by the year 2020. However, the development of more specific and sensitive tests is important for the success of the GPELF. The present study aimed to standardise polymerase chain reaction (PCR)-based systems for the diagnosis of filariasis in serum and urine. Twenty paired biological urine and serum samples from individuals already known to be positive for Wuchereria bancrofti were collected during the day. Conventional PCR and semi-nested PCR assays were optimised. The detection limit of the technique for purified W. bancrofti DNA extracted from adult worms was 10 fg for the internal systems (WbF/Wb2) and 0.1 fg by using semi-nested PCR. The specificity of the primers was confirmed experimentally by amplification of 1 ng of purified genomic DNA from other species of parasites. Evaluation of the paired urine and serum samples by the semi-nested PCR technique indicated only two of the 20 tested individuals were positive, whereas the simple internal PCR system (WbF/Wb2), which has highly promising performance, revealed that all the patients were positive using both samples. This study successfully demonstrated the possibility of using the PCR technique on urine for the diagnosis of W. bancrofti infection.


Selection of a panel of monoclonal antibodies for monitoring residual disease in peripheral blood and bone marrow of interferon-treated hairy cell leukaemia patients.
A panel of monoclonal antibodies (mAbs) directed against B-cell and hairy cell leukaemia (HCL)-associated antigens was used to identify residual hairy cells in the peripheral blood and/or bone marrow samples from 20 patients with HCL, following treatment with interferon-alpha (IFN-alpha) or interferon-beta (IFN-beta). In all cases, hairy cells retained their characteristic phenotype, e.g. positivity for CD22, CD11c, CD25, CD32, and the HCL-associated trimeric protein (t-GP) recognized by the mAbs HML-1, B-ly7, LF61 and Ber-Act8. The most specific marker for identifying a small percentage of hairy cells in peripheral blood cytospins, was t-GP. In alkaline phosphatase/anti alkaline phosphatase (APAAP) stained preparations, t-GP+ hairy cells (provided with large cytoplasm and hairy surface) could be usually distinguished from t-GP+ normal lymphocytes (small-sized cells with smooth surface). In doubtful cases the percentage of residual hairy cells could exactly be estimated by double immunofluorescence staining for CD22 (B-cell marker) and t-GP. The rationale of the test is based on the finding that the small percentage (about 1%) of t-GP+ lymphocytes circulating in the peripheral blood of normal individuals are T-cells of the CD8 subset and not B-cells. The best markers for identifying residual hairy cells in routine bone marrow biopsies were CD45RA (mAb 4KB5) and CD20 (mAb L26). Immunohistological labelling was superior to morphological examination in picking up scattered hairy cells in bone marrow biopsies showing either severe hypoplasia or exuberant hyperplasia of normal haemopoietic series.


Exogenous heat shock protein 70 mediates sepsis manifestations and decreases the mortality rate in rats.
Mammalian responses to bacterial lipopolysaccharide (LPS) from the outer membrane of Gram-negative bacteria can lead to an uncontrolled inflammatory reaction that can be deadly for the host. We checked whether heat shock protein 70 (Hsp70) protein is able to protect animals from the deleterious effects of bacterial LPS by monitoring the effect of exogenous Hsp70 injections before and after LPS administration. Our research with rats demonstrates for the first time that administration of exogeneous Hsp70 before and after LPS challenges can reduce mortality rates and modify several parameters of hemostasis and hemodynamics. Hsp70 isolated from bovine muscles showed significant protective effects against the impaired coagulation and fibrinolytic systems caused by LPS, and reduced the mortality caused by Escherichia coli and Salmonella typhimurium LPS injections significantly. Characteristically, Hsp70 preparations used in the experiments result in different effects when administered before and after an LPS challenge, and the effects of Hsp70 injections also differ significantly depending on the origin of the LPS (E coli vs S typhimurium). Based on our data, mammalian Hsp70 appears to be an attractive target in therapeutic strategies designed to stimulate endogenous protective mechanisms against many deleterious consequences of septic shock by accelerating the functional recovery of susceptible organs in humans.


Control of paralytic poliomyelitis in the United States.
The changing annual vaccination status of the population and the greater than 1,000-fold drop in reported annual incidence of paralytic poliomyelitis between the early 1950s and early 1970s indicate that the control of poliomyelitis in the United States must be attributed to the use of both the inactivated poliovirus vaccine and oral poliovirus vaccine. The containment, in 1972 and 1979, of rare epidemics in poorly vaccinated subpopulations and the existence of only three reported cases of paralytic poliomyelitis clearly attributable to wild poliovirus in the last three years document a major triumph for public health. The continuing occurrence of vaccine-associated paralysis (six or seven reported cases per year, 1980-1982) indicates the necessity, despite the accomplishments, for continued review of the current vaccination strategy.


[Protective effect and mechanism of Baicalin on acute kidney injury in septic mice].
To observe the protective effect and mechanism of different doses of Baicalin (BAI) on acute kidney injury (AKI) in septic mice. According to the random number table, 100 mice were divided into sham operation group (Sham group), cecal ligation and perforation (CLP) induced sepsis model group (CLP group) and BAI pretreatment groups. The mice in BAI pretreatment groups were divided into low-, medium- and high-dose groups (BAI-L+CLP, BAI-M+CLP, BAI-H+CLP groups), with 20 mice in each group. A murine sepsis associated-acute kidney injury (SA-AKI) model was reproduced using CLP. The mice in the Sham group were only opened and closed the abdomen, without ligating or perforating the cecum. The mice in the BAI pretreatment groups were given BAI 25, 50 and 100 mg/kg daily for 3 days, and CLP was performed at 6 hours after administration of BAI at the 3rd day to reproduce sepsis model. The mice in the Sham group and CLP group were given the same amount of distilled water as control. Ten mice were sacrificed at 24 hours after operation to collect orbital blood for renal function determination [serum creatinine (SCr), blood urea nitrogen (BUN), plasma neutrophil gelatinase-associated lipocalin (pNGAL) and plasma kidney injury molecule-1 (pKIM-1)] by enzyme linked immunosorbent assay (ELISA). The kidney tissue was collected to observe the kidney tissue injury under light microscope after hematoxylin-eosin (HE) staining. The TdT-mediated dUTP nick-end labeling (TUNEL) was used to detect the apoptosis of renal tubular epithelial cells. Western blotting was used to detect the expression of cell FLICE like inhibitory protein (c-FLIP) in renal tissue. The remaining 10 mice in each group were used to calculate the survival rate of 7 days after operation. The renal tubular epithelial cells in the CLP group were massively degenerated with necrosis, the renal tubular lumen was significantly expanded, and inflammatory cells were widely infiltrated in the renal interstitium. Furthermore, the renal function deteriorated rapidly. Compared with the CLP group, the renal function of mice pretreated with low dose of BAI was improved, but the difference was not significant. Compared with the CLP group, the renal function in the mice pretreated with medium and high doses of BAI was significantly improved, the SCr, BUN, pNGAL and pKIM-1 were significantly reduced [SCr (μmol/L): 135.16±5.18, 125.70±5.26 vs. 170.42±5.42; BUN (mmol/L): 33.59±1.77, 27.29±1.61 vs. 45.68±1.39; pNGAL (μg/L): 91.29±4.68, 73.40±3.77 vs. 131.50±6.55; pKIM-1 (μg/L): 6.34±0.30, 5.51±0.35 vs. 8.03±0.29; all P < 0.01], the pathological injury of renal tissue was significantly decreased, the apoptotic number of renal tubular epithelial cells was significantly reduced (cells/HP: 16.20±0.49, 13.10±0.66 vs. 29.60±0.49, both P < 0.01), and the expression of c-FLIP protein in renal tissue was significantly increased [c-FLIP protein (c-FLIP/GAPDH): 0.35±0.02, 0.46±0.02 vs. 0.21±0.01, both P < 0.01]. No mouse in the Sham group died within 7 days. Compared with the CLP group, the average survival time of the mice within 7 days in the BAI-L+CLP, BAI-M+CLP and BAI-H+CLP groups was significantly prolonged with a dose-dependent manner (days: 3.5±2.5, 5.4±2.2, 5.9±1.9 vs. 2.1±1.2; Log-Rank test: χ2 = 73.410, P < 0.001). Pretreatment with medium and high doses of BAI can significantly improve the renal function in mice with SA-AKI, decrease the pathological damage and increase the survival of mice, and its mechanism may be related to promoting the increase of c-FLIP protein expression and inhibiting cell apoptosis.


A regional survey of serum creatinine measurement methods and estimated glomerular filtration rate reporting.
Only limited data are available on the diffusion of isotope dilution mass spectrometry (IDMS)-traceable methods used for serum creatinine measurement and on estimated glomerular filtration rate (eGFR) reporting. A questionnaire was addressed to accredited laboratories in Lombardy, Italy, including the following issues: method of creatinine measurement, instrument model, IDMS calibration traceability, reference intervals reported by sex and age, eGFR reporting, eGFR formula used and information about the eGFR value reported in patient records. A parallel questionnaire was addressed to nephrology centers and included the following: knowledge of methods for serum creatinine measurement in their center, usefulness of eGRF reporting and opinions on the need for educational initiatives. Seventy-two percent of 72 laboratories and 89% of 47 nephrology centers responded to the questionnaires. Among the methods used for serum creatinine measurement, 87% were IDMS traceable and 30% were enzymatic. Reference intervals were differentiated by sex and by age in 90% and 42%, respectively. Laboratories reported eGFR in 35% and only when requested in 13%. eGFR was calculated by the Modification of Diet in Renal Disease (MDRD) Study and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations in 88% and 12% of laboratories, respectively, and reporting was accompanied by information on the interpretation of values in 62%. Among nephrologists, 64% thought eGFR reporting useful, 29% were concerned with an excess of unnecessary requests for consultations and 95% expressed a favorable opinion of educational initiatives. Our survey highlights the need for further improvement in serum creatinine measurement and reporting, and for coordinated interventions involving all major stakeholders.


A LY-15, a novel cyclic pentapeptide that inhibits B16 cell proliferation and migration and induces cell apoptosis.
Melanoma is highly resistant to most traditional treatments; therefore, its incidence and mortality rates are rapidly increasing. The effect of a novel sansalvamide A analogue named LY-15 on the growth and induction of apoptosis in B16 cancer cells was investigated in vitro. The inhibitory effects of LY-15 on B16 cells occurred in a concentration- and time-dependent manner. The B16 cells were cultured in various concentrations of LY-15 (5, 15 and 25 µM), and the ameliorating effect of LY-15 was evaluated using apoptotic protein markers B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), caspase-3 and caspase-9. Furthermore, LY-15 effectively inhibited the B16 cell migration, increased the expressions levels of caspase-3, caspase-9 and the pro-apoptotic Bax, and reduced that of the anti-apoptotic Bcl-2. These findings suggested that LY-15 is a promising chemotherapeutic agent against melanoma by inducing apoptosis through the mitochondrial-associated death pathway. In addition, sansalvamide A analogue LY-15 may a significant therapeutic target for the treatment of malignant melanoma cancer.


Prognostic Significance for Long-Term Outcomes Following Radical Prostatectomy in Men with Prostate Cancer: Evaluation with Prostate Imaging Reporting and Data System Version 2.
To retrospectively determine whether the use of the Prostate Imaging Reporting and Data System (PI-RADS) version 2 (v2) helps predict long-term outcomes for prostate cancer (PCa) patients following radical prostatectomy (RP). A total of 166 patients with localized PCa evaluated with multiparametric magnetic resonance imaging (mpMRI) at 3T before RP were enrolled. Three groups were created based on PI-RADS v2 score used to predict clinical outcomes: group A, ≥ 3; group B, ≥ 4; group C, 5. We calculated biochemical recurrence-free survival (RFS) and progression-free survival (PFS). Cox proportion hazards models were used to identify variables predictive of biochemical recurrence and disease progression. During a median follow-up of 9.1 years, biochemical recurrence occurred in 67 patients (40.4%) and disease progression occurred in 55 patients (33.1%). In all groups, 10-year RFS and 10-year PFS were significantly lower for PI-RADS scores ≥ 3, ≥ 4 and 5 than for score < 3, < 4 and < 5 (p <0.05), respectively. In multivariate analysis, PI-RADS score ≥ 3 and score 5 were significant independent risk marker for biochemical recurrence (hazard ratio [HR] = 5.58, p = 0.018; HR = 1.75, p = 0.033) and disease progression (HR = 3.99, p = 0.047; HR = 2.31, p = 0.040). Moderate inter-observer agreement was seen for PI-RADS scoring. PI-RADS v2 may be used to predict long-term outcomes following RP in PCa.


Prospective, double center, 1-year results of adjustable gastric banding with MIDBAND (gastro-gastric suture vs. non-gastro-gastric suture).
Although laparoscopic adjustable gastric banding (LAGB) is a popular bariatric procedure, few comprehensive studies have been investigated on the use of non-gastro-gastric sutures (NGGSs) for decreasing postoperative complications. This study aimed to assess and compare the safety and effectiveness of MIDBAND with or without gastro-gastric sutures (GGSs). Between February 2013 and March 2014, 41 severely obese patients underwent primary LAGB using pars flaccid technique at double center in South Korea. Excess weight loss, operative time and postoperative complications were assessed and compared between a GGS group (group 1) and a NGGS group (group 2), and patients were followed monthly for 1 year. Mean body mass indices in groups 1 and 2 were 38.4 ± 4.7 and 38.9 ± 5.0 kg/m2, respectively, and mean percentage excess weight losses (%EWLs) were 59.9% ± 28.4% and 50.9% ± 20.0%, respectively, at 6 months, and 75.8% ± 26.6% and 72.5% ± 27.5%, respectively, at 12 months, and these intergroup differences of %EWL were not significant (P = 0.256 and P = 0.704, respectively). Mean operative time (57.2 minutes) was shorter in group 2 than in group 1 (79.2 minutes) (P < 0.001). In terms of complications, pouch dilatation rates were similar in the 2 groups, and no case of gastric band erosion was encountered. Operative time was shorter in the NGGS group, and pouch dilatation rates and %EWL were similar in the 2 groups. We conclude NGGS using MIDBAND is both straightforward and effective. A long-term prospective comparative study is needed to demonstrate the safety and efficacy of NGGS.


[The ultrasound characteristics of kidneys in children and adolescents with diabetes mellitus type 1].
The aim of the study was to compare ultrasound findings of morphometric measurements and registration of Doppler signs of kidneys between children and adolescents with diabetes mellitus type 1 (DMT1) with microalbuminuria, and metabolic control with duration of the disease. Retrospective-prospective study included 80 patients, who got DMT1 in the age from 2 to 16 years. In relation to the duration of the disease, all patients were divided into two groups: the first was whose illness had lasted less than 10 years, the second group was with duration of DMT1 more than 10 years. In patients with duration of DMT1 more than 10 years, the frequency of microalbuminuria, pathological findings of the volume of right kidney, and higher HbA1C were significantly greater. The significant difference was found in the frequency of pathological findings of the resistance index (RI) in the interlobar arteries in both kidneys. Alongside microalbuminuria, monitoring the dimension and volume of the kidneys may indicate the existence of the early phases of diabetic nephropathy.


Hematometra formation- a rare complication of cesarean delivery.
Hematometra resulting from partial or complete obstruction of lower genital tract may be congenital or acquired. Commonest congenital causes are imperforate hymen and transverse vaginal septum. Acquired causes are senile atrophy of endocervical canal, scarring of the isthmus by synechiae, radiation and endocervical malignancy or due to surgical procedures. Various surgical procedures associated with hematometra are dilatation and curettage, cone biopsy, endometrial ablation, cryocoagulation and electrocautery. Hematometra following an abortion or cesarean delivery is rare. We report a case of hematometra following obstruction of outflow tract due to prior cesarean delivery.


Prognostic significance of preoperative albumin to fibrinogen ratio associated nomograms in patients with breast invasive ductal carcinoma.
Plasma albumin to fibrinogen ratio is involved in human cancer, but its prognostic significance in breast cancer is controversy. In the context of breast invasive ductal carcinoma, this research aims to retrospectively evaluate by preoperative plasma albumin to fibrinogen ratio (AFR) and forecast oncological outcome and recurrence.This retrospective study comprised 230 patients with non-metastatic breast invasive ductal carcinoma who underwent surgery between January 2009 and April 2012 in Fourth Hospital of Hebei Medical University. Patients were categorized base on an optimal value of preoperative plasma fibrinogen (Fib) and albumin. Progression-free and cancer-specific survival were assessed using Kaplan-Meier method. The associations between albumin to fibrinogen ratio and clinical outcomes were assessed with univariate and multivariate analysis. A number of risk factors were used to form nomograms to evaluate survival, and Harrell concordance index (C-index) was used to evaluate the predictive accuracy.Plasma AFR was significantly associated with diminished disease-free survival (DFS) and overall survival (OS). Multivariate analysis revealed that plasma AFR was an independent prognostic indicator for DFS (HR = 1.346; 95% CI: 1.107-1.636; P = .03) and overall survival (OS) (HR = 1.485; 95% CI: 1.106-1.993; P = .008). Two prediction model of 3-, 5-years OS and DFS based on the AFR was developed.Elevated preoperative plasma AFR is an independent prognostic factor for oncological outcomes in patients with breast invasive ductal carcinoma. The formulated nomogram showed superior predictive accuracy for DFS and OS.


Are Unique Regional Factors the Missing Link in India's COVID-19-Associated Mucormycosis Crisis?
The exact cause of the disproportionate increase in COVID-19-associated mucormycosis (CAM) cases in India remains unknown. Most researchers consider the major cause of India's CAM epidemic to be the conjunction of the COVID-19 pandemic and associated corticosteroid treatment with the enormous number of Indians with diabetes mellitus (DM). However, excess CAM cases were not seen to the same extent in the Western world, where diabetes is prevalent and corticosteroids are also used extensively for COVID-19 treatment. Herein, we hypothesize that previously overlooked environmental factors specific to India were important contributors to the country's CAM epidemic. Specifically, we propose that the spread of fungal spores, mainly through fumes generated from the burning of Mucorales-rich biomass, like cow dung and crop stubble, caused extensive environmental exposure in the context of a large population of highly vulnerable patients with DM and COVID-19. Testing this hypothesis with epidemiologic studies, phylogenetic analyses, and strategic environmental sampling may have implications for preventing future epidemics.


Liver disease in pregnancy.
Development of liver diseases during pregnancy is not uncommon. They are caused by either a disorder that is unique to pregnancy or an acute or chronic liver disease that already exists or coincidentally develops as a comorbidity of pregnancy. Liver diseases unique to pregnancy include hyperemesis gravidarum; hypertensive disorders of pregnancy, such as pre-eclampsia/eclampsia; hemolysis, elevated liver enzymes, and low platelet count syndrome; intrahepatic cholestasis of pregnancy; and acute fatty liver of pregnancy. Chronic liver diseases that affect pregnancy, or are affected by pregnancy, mainly include autoimmune liver diseases and non-alcoholic fatty liver disease. Prompt diagnosis and management of liver diseases in pregnancy, while very challenging, is extremely important, as they might cause adverse maternal and fetal outcomes. Therefore, a multidisciplinary, collaborative approach involving both hepatologists and obstetricians is required. In this review article, the up-to-date epidemiology, etiology, clinical features, and outcomes of liver diseases in pregnancy are discussed, to promote a deeper understanding among physicians, and subsequently improved outcomes.


A new model for study of pancreatic exocrine secretion: the tethered pancreatic fistula rat.
Diversion and recirculation of bile and pancreatic juice in rats are done in studies of pancreatic exocrine secretion. Previously, the modified Bollman cage was used to restrain rats with bile and pancreatic fistulas. To mimic physiologic conditions as closely as possible and to develop a more humane model, we designed a partial-restraint tethering system to study pancreatic exocrine secretion. Eight rats were prepared with biliary pancreatic, and duodenal fistulas, of which five were given enteral supplements via a gastric fistula and three were given saline supplements via a jugular venous line. Catheters exited at the nape of the neck and passed through the hollow of a cable coil that tethered the rat. On the fourth postoperative day pancreatic juice flow and protein output were studied. The tethering system allowed grooming, feeding, and ample mobility. This model of the tethered pancreatic fistula rat is a more human model for studies of pancreatic exocrine secretion in conscious rats, compared with the Bollman cage system of near total restraint.


Structural biology of the writers, readers, and erasers in mono- and poly(ADP-ribose) mediated signaling.
ADP-ribosylation of proteins regulates protein activities in various processes including transcription control, chromatin organization, organelle assembly, protein degradation, and DNA repair. Modulating the proteins involved in the metabolism of ADP-ribosylation can have therapeutic benefits in various disease states. Protein crystal structures can help understand the biological functions, facilitate detailed analysis of single residues, as well as provide a basis for development of small molecule effectors. Here we review recent advances in our understanding of the structural biology of the writers, readers, and erasers of ADP-ribosylation.


Prognostic Values of Prothrombin Time and Inflammation-Related Parameter in Acute Ischemic Stroke Patients After Intravenous Thrombolysis with rt-PA.
In previous studies, prothrombin time (PT), systemic inflammation response index (SIRI) and systemic immune inflammation Index (SII) levels might be the prognostic factors for patients with ischemic stroke. However, the association between these coagulation and inflammation biomarkers and prognosis in patients with acute ischemic stroke (AIS) who undergo intravenous thrombolysis (IVT) with recombinant tissue plasminogen activator (rt-PA) remains unclear and needs further study. Thus, this study aimed to investigate the relationship between these biomarkers and clinical prognosis after IVT in AIS patients. We included patients at the Hebei general hospital diagnosed with AIS who received standard-dose IVT with rt-PA from September 2017 to August 2022. Demographic information, vascular risk factors, laboratory test results, and other stroke-related data were collected for analysis. Clinical outcomes included short-term outcome at 24 h and functional outcome at 3 months. We enrolled 281 patients in this study. In total, 16 patients had END within 24 h, and 106 patients had an unfavorable outcome at the 3-month visit. In the multivariate analysis, PT level (OR = 1.833; 95% CI: 1.161-2.893; P = 0.009), SIRI level (OR = 2.166; 95% CI: 1.014-4.629; P = 0.046) and SII level (OR = 1.002; 95% CI: 1.000-1.003; P = 0.021) were independently associated with 3-month poor outcome in AIS patients with IVT. In conclusion, the higher PT, SIRI and SII levels were independently associated with poor prognosis in AIS patients after IVT. Additionally, PT, SIRI and SII all can be novel short-term prognostic biomarkers for AIS patients treated with IVT.


DRESS syndrome-associated acute necrotizing eosinophilic myocarditis with giant cells.
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is an uncommon drug hypersensitivity reaction caused by a wide variety of agents. It has a characteristic latent period between 2 and 8 weeks from the onset of drug ingestion followed by a slow resolution with the potential for relapse. Despite being a potentially fatal disease, little is understood about its variable clinical presentation and why it can present long after removal of the offending drug. Visceral organ involvement typically occurs, but rarely results in clinically manifested cardiac injury. In its most aggressive form, acute necrotizing eosinophilic myocarditis (ANEM) can present with DRESS. We present an unusual case of DRESS syndrome due to lamotrigine with confirmed ANEM showing both eosinophils and rare giant cell infiltrates on endomyocardial biopsy. Although lamotrigine has been reported to cause DRESS, it has not been previously implicated as a cause of ANEM.


Pore Structure of Grain-Size Fractal Granular Material.
Numerous studies have proven that natural particle-packed granular materials, such as soil and rock, are consistent with the grain-size fractal rule. The majority of existing studies have regarded these materials as ideal fractal structures, while few have viewed them as particle-packed materials to study the pore structure. In this study, theoretical analysis, the discrete element method, and digital image processing were used to explore the general rules of the pore structures of grain-size fractal granular materials. The relationship between the porosity and grain-size fractal dimension was determined based on bi-dispersed packing and the geometric packing theory. The pore structure of the grain-size fractal granular material was proven to differ from the ideal fractal structure, such as the Menger sponge. The empirical relationships among the box-counting dimension, lacunarity, succolarity, grain-size fractal dimension, and porosity were provided. A new segmentation method for the pore structure was proposed. Moreover, a general function of the pore size distribution was developed based on the segmentation results, which was verified by the soil-water characteristic curves from the experimental database.


Sleep time following anesthesia in mouse lines selected for resistance or susceptibility to fescue toxicosis.
In previous work, a mouse line selected for resistance (R) to fescue toxicosis had higher activities of two hepatic Phase II detoxification enzymes than a mouse line selected for fescue toxicosis susceptibility (S). The primary objective of the present study was to determine whether those same lines also differed in hepatic Phase I enzyme activity, estimated from sleep time (ST) following sodium pentobarbital anesthesia. Additional objectives were to determine whether ST differences between lines were modulated by endophyte-infected fescue in the diet (with or without an enzyme inducer) and whether ST of individual mice was correlated with the effect of a toxin-containing diet on the postweaning growth of those mice. In Exp. I, 24 males from each line were randomly assigned to each of five diets: control (commercial rodent food meal); E+ (50% endophyte-infected fescue seed, 50% control); E+P (the E+ diet supplemented with 1,000 ppm phenobarbital); E- (50% endophyte-free fescue seed, 50% control); and E-P (the E- diet supplemented with 1,000 ppm phenobarbital). After 4 wk on these diets, ST was measured on all the mice. A second ST was recorded on each mouse by randomly sampling one-fourth of the population after 1, 2, 3, or 4 wk on a pelleted rodent food diet. Regardless of diet, R mice had shorter first and second ST than S mice (P < 0.01), suggesting higher hepatic Phase I microsomal enzyme activity. Mice on both phenobarbital-supplemented diets had shorter first ST than mice whose diets did not include that microsomal enzyme inducer (P < 0.01). In Exp. II, ST was measured on male and female R and S mice (n = 280) after they had been fed the E- diet for 2 wk, then the E+ diet for 2 wk, and then a pelleted rodent food diet for 2 wk. Growth response to the E+ diet was the percentage of reduction in gain on the E+ diet compared to gain on the E- diet the previous 2 wk. As in Exp. I, S mice slept longer than R mice (P < 0.01). The residual correlation between ST and gain reduction associated with the E+ diet equaled 0.04. Thus, an animal's apparent Phase I enzyme activity did not predict its growth rate depression on the toxin-containing diet. Based on these and previous studies, divergent selection for toxicosis response in mice was successful partially by causing divergence in activities of hepatic Phase I and II detoxification enzymes.


The effect of xylitol on dental caries and oral flora.
Dental caries, the most chronic disease affecting mankind, has been in the limelight with regard to its prevention and treatment. Professional clinical management of caries has been very successful in cases of different severities of disease manifestations. However, tertiary management of this disease has been gaining attention, with numerous methods and agents emerging on a daily basis. Higher intake of nutritive sweeteners can result in higher energy intake and lower diet quality and thereby predispose an individual to conditions like obesity, cardiovascular disorders, and type 2 diabetes mellitus. Non-nutritive sweeteners have gained popularity as they are sweeter and are required in substantially lesser quantities. Xylitol, a five-carbon sugar polyol, has been found to be promising in reducing dental caries disease and also reversing the process of early caries. This paper throws light on the role and effects of various forms of xylitol on dental caries and oral hygiene status of an individual.


Subjective and objective evaluation of shoulder muscle fatigue.
In order to relate EMG signs of localized muscle fatigue to subjectively perceived muscle fatigue, a study was undertaken on 20 healthy volunteers exposing their right trapezius muscle by raising the arm to 90 degrees of abduction. Every person performed two contractions: 0 kg hand load during 5 min and 2 kg hand load during 2.5 min. Surface EMG was recorded and analysed with respect to RMS amplitude and mean power frequency (MPF). Subjective muscle fatigue was estimated with a psychophysical rating scale (Borg's CR-10 Scale). At high load level we found a significant correlation between MPF and the CR-scores (r = -0.46), but at low load level there was no correlation. At high load level there was a linear decrease of MPF with increasing load dose, but at low load level the MPF did not change, despite significant subjective fatigue. There was a linear rise of the CR-score with increasing load dose, more pronounced at high load level. It was concluded, that at low load levels common in working life, MPF and subjective scores seem to provide different fatigue information. Moreover, the MPF did not seem to work as a valid estimator of muscle fatigue at this low load level. Caution is recommended if it is to be used in static low-load situations.


Successful preventive treatment of congenital heart block during pregnancy in a woman with systemic lupus erythematosus and anti-Sjögren's syndrome A/Ro antibody.
Congenital heart block (CHB) that is a manifestation of neonatal lupus syndrome (NLS) carries a poor prognosis. The treatment response of established heart block in NLS is usually unsatisfactory. Preventive treatment during pregnancy, however, before the critical period of cardiac development, can prevent the development of CHB. A Taiwanese woman with systemic lupus erythematosus (SLE) was positive for anti-Sjögren's syndrome A (SSA)/Ro antibody. Her first pregnancy resulted in intra-uterine fetal death. Her second pregnancy resulted in CHB, despite dexamethasone treatment, and neonatal death at age 1 day despite pacemaker implantation. During her third pregnancy, dexamethasone was given starting at week 10, azathioprine at week 18, and plasmapheresis was performed every other day for 5 times starting at week 20 of gestation. Cesarean section was performed due to oligohydramnion at week 31 of gestation and a healthy girl was delivered. This case suggests that judicious use of fluorinated glucocorticoids, immunosuppressants, and plasmapheresis may prevent development of CHB in pregnant women with SLE who are anti-SSA/Ro antibody positive and have previous children with CHB.